The overall objective of this research proposal is to further our understanding of the process of focal seizure development. In particular, we hope to elucidate some of the mechanisms underlying the propagation of the epileptiform after discharge. To study these mechanisms, we have developed an animal model which we term "kindling antagonism". In this model, seizure development is induced concurrently at two foci. The consistent outcome of this procedure is that one focus becomes dominant and develops generalized seizures, while seizure development from the other focus is suppressed. We believe that understanding the mechanisms responsible for kindling antagonism will provide significant insight into the process of epileptogenesis. During the past grant period we demonstrated that the development of kindling antagonism is dependent on norepinephrine (NE). Furthermore, our data suggest that the critical region of NE innervation for expression of the phenomenon resides in the hindbrain. Our first specific aim is to continue our assessment of the importance of NE in the development and subsequent maintenance of seizure suppression at antagonized sites. We will ask the following questions: (1) What is the importance of hindbrain hypertrophy of NE innervation for the development of kindling antagonism? (2) What is the importance of cerebellar NE in the development of kindling antagonism? (3) Once a condition of antagonism is established in the presence of NE, does NE continue to play a necessary role in the maintenance of seizure suppression? Also, during the last grant period we have done preliminary studies which indicate that kindling antagonism is dependent on cerebellar projections via the superior cerebellar peduncle. Therefore, our second specific aim is to investigate the role of the cerebellum in the development and maintenance of seizure suppression. We will ask the following questions: (1) In our original, preliminary lesions aimed at the superior cerebellar peduncle, was it only the cerebellar projections which were critical for the development of kindling antagonism, or are there other critical areas within the surrounding brainstem parenchyma? (2) Which specific afferent or efferent projections of the cerebellum are important for the development of kindling antagonism? (3) Is the cerebellum important for the continued maintenance of seizure suppression after a condition of kindling antagonism has been developed?